Immunophilins are cytosolic proteins endowed with peptidyl-prolyl-cis-trans isomerase (PPIase or rotamase) activity. This family of proteins behave as chaperone molecules causing cis-trans isomerization of specific prolyl amide bonds that could be a rate limiting step in the correct folding of certain proteins. They are also involved in many cellular signal transduction pathways as partners in multiprotein complexes for which binding in the rotamase active site, but not rotamase activity per se, appears to be important (Ruhlmann, et al., Immunobiol., 198, pp. 192-206 (1998)). Immunosuppressive drugs such as FK506, rapamycin and cyclosporin A bind to specific groups of immunophilins. FK506 and rapamycin bind to the so-called FK506-binding proteins (e.g. FKBP-12, -25, -52), whereas the cyclophilins bind to cyclosporin A. It has been shown that binding to the 12kD immunophilin FKBP12 is necessary for FK506 to elicit its immunosuppressive activity. Subsequently, it was also found that FK506 has two binding domains: one that binds to FKBP12 and the other (the effector domain) for the complex of FK506 and FKBP12 that binds to the serine/threonine phosphatase, calcineurin. This complexation inhibits calcineurin and prevents the proliferation of T-lymphocytes, causing immunosuppression. Rapamycin has an effector domain of a different structure, and its complex with FKBP12 binds to a different target protein that, however, has the same effect of inhibiting T-lymphocyte proliferation. For a review, see S. L. Schreiber, et al., Tetrahedron, 48, pp. 2545-2558 (1992).
While FK506 exhibits immunosuppressive effects, analogs lacking the calcineurin binding effector domain are devoid of immunosuppressive activity. Many small molecules that contain the essential elements of the FKBP12 binding domain of FK506 but lack the calcineurin binding domain were found to retain high affinity binding to FKBP12, and behave as rotamase inhibitors (D. S. Yamshita, et al., Bioorg. Med. Chem. Lett., 4, pp. 325-328 (1994); D. M. Armistead, et al., Acta Cryst. D, 51, pp. 522-528 (1995)).
FK506 has been shown to possess neurotrophic properties in vitro and in vivo (W. E. Lyons, et al., Proc. Natl. Acad. Sci USA, 91, pp. 3191-3195 (1994); B. G. Gold, et al., J. Neurosci., 15, pp. 7509-7516 (1995)). However, its immunosuppressive properties as well as other serious side effects are drawbacks to its use as a neuroregenerative agent. Recently, in vitro studies in PC12 cells, SY5Y cells, and chick sensory dorsal root ganglion explant cultures have shown that small molecule, nonimmunosuppressive FKBP12 rotamase inhibitors also promote neurite outgrowth, and a number of these compounds have shown utility in reversal of CNS lesioning and nerve crush in animal models (G. S. Hamilton, et al., Curr. Pharm. Design, 3, pp. 405-428 (1997); B. G. Gold, et al., Exp. Neurol., 147, pp. 269-278 (1997)). Thus, while the calceineurin binding domain of FK506 is necessary for immunosuppressive activity, it is not required for neurotrophic activity.
A 10-50 fold elevated expression of immunophilins in the central nervous system in comparison with the immune system is well documented (S. H. Snyder, et al., Nature Med., 1, pp. 32-37 (1995)). Recently, augmented expression of FKBP12 m-RNA following facial nerve crush and sciatic nerve lesions was established in facial and lumbar motor neurons. The observed augmentation paralleled the enhanced expression of growth associated protein GAP43 mRNA (B. G. Gold, et al., Neurosci. Lett., 241, pp. 25-28 (1998)). These observations make FKBP12 an attractive target for developing nonimmunosuppressive rotamase inhibitors which promote neurite outgrowth. Such compounds are potential therapeutics to reverse neuronal damage caused by neurodegenerative disease or physical trauma.
There have been disclosures of related compounds for overcoming multidrug resistance (MDR) or as immunosuppressants such as:
WO 94/07858 published Apr. 14, 1994 PA1 WO 92/19593 published Nov. 12, 1992 PA1 U.S. Pat. No. 5,622,970 granted Apr. 22, 1997 PA1 U.S. Pat. No. 5,330,993 granted Jul. 19, 1994 PA1 U.S. Pat. No. 5,192,773 granted Mar. 9, 1993 PA1 U.S. Pat. No. 5,516,797 granted May 14, 1996 PA1 WO 92/21313 published Dec. 10, 1992 PA1 European Application 564924 published Oct. 13, 1993 PA1 European Application 405994 published Jan. 2, 1991 PA1 WO 96/40140 published Dec. 19, 1996 PA1 WO 96/40633 published Dec. 19, 1996 PA1 WO 97/16190 published May 9, 1997 PA1 WO 96/41609 published Dec. 27, 1996 PA1 U.S. Pat. No. 5,696,135 granted Dec. 9, 1997 PA1 WO 97/36869 published Oct. 9, 1997 PA1 U.S. Pat. No. 5,721,256 granted Feb. 24, 1998 PA1 U.S. Pat. No. 5,654,332 granted Aug. 5, 1997 PA1 WO 98/13343 published Apr. 2, 1998 PA1 WO 98/13355 published Apr. 2, 1998 PA1 wherein W is CH.sub.2, O, NH, or N--(C.sub.1 -C.sub.4)-alkyl; PA1 wherein J is hydrogen, (C.sub.1 -C.sub.4)-alkyl or benzyl; PA1 wherein K is (C.sub.1 -C.sub.4)-straight or branched alkyl, benzyl or cyclohexylmethyl, or wherein J and K may be taken together to form a 5-7 membered heterocyclic ring which may contain a heteroatom selected from the group consisting of O, S, SO, and SO.sub.2 ; PA1 wherein the stereochemistry at carbon position 1 is R or S; PA1 wherein Z is Q or --(CH.sub.2)m --C(H)Q'A; PA1 wherein m is 0-3; PA1 wherein Q is hydrogen, CHL--Ar, (C.sub.1 -C.sub.6)-straight or branched alkyl, (C.sub.2 -C.sub.6)-straight or branched alkenyl, (C.sub.5 -C.sub.7)-cycloalkyl, (C.sub.5 -C.sub.7)-cycloalkenyl, Ar substituted (C.sub.1 -C.sub.6)-alkyl, (C.sub.2 -C.sub.6)-alkenyl or ##STR2## PA1 wherein L and G are independently hydrogen, (C.sub.1 -C.sub.6)-straight or branched alkyl, (C.sub.2 -C.sub.6)-straight or branched alkenyl; PA1 wherein T is Ar or substituted cyclohexyl with substituents at positions 3 and 4 which are independently selected from the group consisting of hydrogen, hydroxyl, O--(C.sub.1 -C.sub.4)-alkyl or O--(C.sub.2 -C.sub.4)-alkenyl and carbonyl; PA1 wherein D is (C.sub.1 -C.sub.6)-straight or branched alkyl, (C.sub.2 -C.sub.6)-straight or branched alkenyl, (C.sub.5 -C.sub.7)-cycloalkyl or (C.sub.5 -C.sub.7)-cycloalkenyl substituted with (C.sub.1 -C.sub.4)-straight or branched alkyl or (C.sub.2 -C.sub.4)-straight or branched alkenyl, O--(C.sub.1 -C.sub.4)-straight or branched alkyl, O--(C.sub.2 -C.sub.4)-straight or branched alkenyl, 2-indolyl, 3-indolyl, [(C.sub.1 -C.sub.4)-alkyl or (C.sub.2 -C.sub.4)-alkenyl]-Ar or Ar; PA1 wherein Ar is a carbocyclic aromatic group selected from the group consisiting of phenyl, 1-naphthyl, 2-naphthyl, indenyl, azulenyl, fluorenyl, and anthracenyl; or a heterocyclic aromatic group selected from the group consisting of 2-furyl, 3-furyl, 2-thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, 1,2,3-oxadiazolyl, 1,2,3-triazolyl, 1,3,4-thiadiazolyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1,3,5-triazinyl, 1,3,5-trithianyl, indolizinyl, indolyl, isoindolyl, 3H-indolyl, indolinyl, benzo[b]furanyl, benzo[b]thiophenyl, 1H-indazolyl, benzimidazolyl, benzthiazolyl, purinyl, 4H-quinolizinyl, quinolinyl, isoquinolinyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl, phenothiazinyl, and phenoxazinyl; PA1 wherein Ar may contain one to three substituents which are independently selected from the group consisting of hydrogen, halogen, hydroxyl, hydroxymethyl, nitro, trifluoromethyl, trifluoromethoxy, (C.sub.1 -C.sub.6)-straight or branched alkyl, (C.sub.2 -C.sub.6)-straight or branched alkenyl, O--[(C.sub.1 -C.sub.4)-straight or branched alkyl], O-benzyl, O-phenyl, 1,2-methylenedioxy, amino, carboxyl, N--[(C.sub.1 -C.sub.5)-straight or branched alkyl or (C.sub.2 -C.sub.5)-straight or branched alkenyl] carboxamides, N,N-di-[(C.sub.1 -C.sub.5)-straight or branched alkyl or (C.sub.2 -C.sub.5)-straight or branched alkenyl] carboxamides, N-morpholinecarboxamide, N-benzylcarboxamide, N-thiomorpholinocarboxamide, N-picolinoylcarboxamide, O--X, CH.sub.2 --(CH.sub.2).sub.p --X, O--(CH.sub.2).sub.p --X, (CH.sub.2).sub.p --O--X, and CH.dbd.CH--X; PA1 wherein X is 4-methoxyphenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazyl, quinolyl, 3,5-dimethylisoxazoyl, isoxazoyl, 2-methylthiazoyl, thiazoyl, 2-thienyl, 3-thienyl, or pyrimidyl; PA1 wherein p is 0-2; PA1 wherein Q' and A are independently hydrogen, Ar, (C.sub.1 -C.sub.10)-straight or branched alkyl, (C.sub.2 -C.sub.10)-straight or branched alkenyl or alkynyl, (C.sub.5 -C.sub.7)cycloalkyl substituted-straight (C.sub.1 -C.sub.6)-straight or branched alkyl, (C.sub.2 -C.sub.6)-straight or branched alkenyl or alkynyl, (C.sub.5 -C.sub.7)-cycloalkenyl substituted (C.sub.1 -C.sub.6)-straight or branched alkyl, (C.sub.2 -C.sub.6)-straight or branched alkenyl or alkynyl, or Ar substituted (C.sub.1 -C.sub.6)-straight or branched alkyl, (C.sub.2 -C.sub.6)-straight or branched alkenyl or alkynyl wherein, in each case, any one of the CH.sub.2 groups of said alkyl, alkenyl or alkynyl chains may be optionally replaced by a heteroatom selected from the group consisting of O, S, SO, SO.sub.2 and NR, wherein R is selected from the group consisting of hydrogen, (C.sub.1 -C.sub.4)-straight or branched alkyl, (C.sub.2 -C.sub.4)-straight or branched alkenyl or alkynyl, and (C.sub.1 -C.sub.4)-bridging alkyl wherein a bridge is formed between the nitrogen and a carbon atom of said heteroatom-containing chain to form a ring, and wherein said ring is optionally fused to an Ar group; or ##STR3## PA1 wherein G' is hydrogen, (C.sub.1 -C.sub.6)-straight or branched alkyl or (C.sub.2 -C.sub.6)-straight or branched alkenyl or alkynyl.
Other prior art disclosing related compounds having neurotrophic activity are:
Since there are relatively few FKBP12-binding compounds that are known to stimulate neurite growth, there remains a great need for additional neurotrophic, FKBP12-binding compounds.